Fluoroalkyl substituents have become increasingly important in the research and development of biologically active compounds including pharmaceuticals. A number of existing blockbuster pharmaceuticals include a fluoroalkyl substituent. Incorporation of a trifluoromethyl group into an organic molecule can favorably change its lipophilicity and pharmacokinetics. In addition, investigations of an analogue of a compound in which a methyl group has been replaced by a trifluoromethyl group can provide insights into the biological activity of the compound.
Although the effect of the trifluoromethyl substituent on biological activity and pharmacokinetics has been studied, methods to incorporate the trifluoromethyl group into aromatic compounds are limited. Conventionally, aryl compounds have been substituted with trifluoromethyl groups through the reaction of aryl carboxylic acids with SF4, or through the fluorination of a trichloromethyl substituent of an aryl compound with Swart's reagent (SbF3). The SF4 and SbF3 reagents, however, are toxic and difficult to handle.
In another approach, trifluoromethyl groups have been incorporated into aromatic compounds using palladium-mediated or palladium-catalyzed reactions. Each of these approaches, however, has at least one disadvantage, such as limited toleration of functionality, high loadings of an expensive phosphine ligand, high loadings of palladium, high temperature conditions, or the need for an expensive CF3 source.
In yet another approach, trifluoromethyl groups have been incorporated into aromatic compounds using copper(I) reagents and catalysts. These reactions, however, also have severe limitations for synthetic applications. Reactions of a trifluoromethylcopper complex prepared from CuX and either Cd(CF3)X or Zn(CF3)X have been reported, as have reactions using CuI and trialkyl(trifluoromethyl)silanes with KF as an activator. These methods, however, involve toxic cadmium reagents and HMPA solvent to facilitate formation of CuCF3, and/or occur with limited functional group compatibility and in poor yields with electron-rich aryl halides. Trifluoromethylcopper compounds ligated by N-heterocyclic carbenes (NHC) are not useful for preparative work because the compounds are prepared by a three-step synthesis starting with an expensive NHC ligand. Trifluoromethylation catalyzed by copper iodide using methyl fluorosulfonyldifluoroacetate FSO2CF2CO2Me as the source of CF3 generates toxic SO2 and MeI and cannot be extended to higher perfluoroalkyl groups. Trifluoromethylation of aryl iodides with a catalytic amount of copper iodide ligated by 1,10-phenanthroline requires the expensive TESCF3 reagent, and high yields were obtained only with electron-deficient aromatic halides.
Accordingly, it would be desirable to form fluoroalkylarenes under mild conditions in a manner that would tolerate a wide variety of functional groups. Preferably such a fluoroalkylation method would utilize reagents that are readily accessible, relatively inexpensive, and less toxic than conventional fluoroalkylation reagents.